Dysautonomia Due to Reduced Cholinergic Neurotransmission Causes Cardiac Remodeling and Heart Failure

Abstract

Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.

Supplemental material for this article may be found at http://mcb.asm.org/.

We thank Sanda Raulic and Jue Fan for mouse husbandry and genotyping at the University of Western Ontario, Richard Premont and Raul Gainetdinov (Duke University Medical Center) for advice on GRK PCR, and Brian Collier (McGill University) and R. Jane Rylett (University of Western Ontario) for comments on earlier versions of the manuscript.

This work was supported by the Heart and Stroke Foundation of Ontario (grant NA 6656 to R.G., S.G., V.F.P., and M.A.M.P.), CIHR (grants MOP-82756 to R.G. and MOP-89919 to V.F.P. and M.A.M.P.), NIH-Fogarty grant R21 TW007800-02 (to M.A.M.P., V.F.P., and M.G.C.), PRONEX-FAPEMIG (to M.A.M.P., V.F.P., and S.G.), CNPq (to S.G., J.S.C., V.F.P., and M.A.M.P.), FAPEMIG, and Instituto do Milenio Toxins/MCT (to M.V.G., M.A.M.P., V.F.P., A.P.A., and S.G.). R.P. and C.A.S.M. received postdoctoral fellowships from the Department of Foreign Affairs and International Trade (Canada). R.G. is supported by a New Investigator Award from the Heart and Stroke Foundation of Canada.